MON-261 Investigation of GNAS1 Gene Mutations and Expression Patterns of Fibroblast Growth Factor 23 Protein in McCune-Albright Syndrome

Abstract

McCune-Albright syndrome (MAS) is characterized by the clinical triad of polyostotic fibrous dysplasia, café-au-lait spots and gonadotropin-releasing hormone-independent precocious puberty, caused by somatic activating mutations of the GNAS1 gene in a mosaic distribution. Overproduction of FGF23 (fibroblast growth factor 23) secreted by bone lesions has been recently reported to be responsible for hypophosphatemic vitamin D-resistant rickets in this disease. This study aimed to analyze the GNAS1 gene in bone lesions of MAS and to investigate the expression patterns of FGF23 protein. Patient and methods: The patient was a 12-year-old boy with MAS. He had polyostotic fibrous dysplasia, hypophosphatemia, café-au-lait spots, and hyperthyroidism and was receiving methimazole. He underwent surgical interventions 3 times for distortions of long bones. We analyzed GNAS1 gene by using peripheral blood cells, resected bone, and muscle tissues. To evaluate FGF23 expression, we performed immunohistochemistry using the resected bone tissue and RT-PCR using the resected bone and muscle tissues along with the measurement of FGF23 in the pre- and post-operative serum. Results: Although no mutations in the GNAS1 gene were found in either peripheral blood cells or muscle tissue, a known activating mutation of p.R201H was heterozygously detected in the bone tissue. Although immunohistochemistry for FGF23 was negative in the first specimen of resected bone tissue, FGF23 mRNA was detected by RT-PCR in the second specimen, but not in muscle tissue. Changes in serum FGF23 levels after each bone resection were as follows: 100 → 54 pg/ml (1 day after first resection), 74 → 102 pg/ml (2 weeks after second resection), and 102 → 85 pg/ml (2 days after third resection). There were no changes in the serum phosphorus level, %TRP, or TmP/GFR after surgery. Discussion and conclusion: We detected GNAS1 gene mutation in only the bone lesion, reflecting its mosaic distribution. The reason why FGF23 mRNA was detected in the second resected bone tissue on RT-PCR despite the negative immunohistochemistry in the first one was attributed to differences in sensitivity between the methods or site-specific expression patterns. The serum level of FGF23 decreased through 2 days after surgery, but did not enter the normal range, and hypophosphatemia did not improve. Fibrous dysplasia was suggested to spread to the entire bone. Moreover, FGF23 increased 2 weeks after surgery probably because the production recovered in the remained lesion. Bone resection did not effectively decrease the FGF23 level.